Common variable immunodeficiency (CVID) is the most common human primary immunodeficiency. Patients with CVID suffer from recurrent infections and have an increased incidence of autoimmune disorders and lymphoid malignancies. TACI is a receptor for BAFF and APRIL expressed mainly on B cells, and plays an important role in B cell differentiation and antibody production to type II T independent (Tl) antigens. TACI is mutated in a subgroup of patients with CVID. Two missense mutations, C104R in the extracellular domain, which disrupts ligand binding, and A181E in the transmembrane domain, which abolishes signaling, account for the majority of TACI mutations in CVID. Most CVID patients with these two mutations are heterozygous. The central theme of this project is to establish the functional relevance of TACI mutations observed in CVID. Our preliminary data suggests that TACI oligomerizes on the cell surface and that TACI ligation synergizes with CD40 and TLRs to cause B cell differentiation. Preliminary data in TACI+/ mice that express mutant TACI transgenes support haploinsufficiency as the mechanism of action of the C104R mutation, and suggest that the A181Emutation could exert a dominant negative (DN) effect Our overall hypothesis is that heterozygous TACI mutations found in CVID impair TACI function because of haploinsufficiency or a DN effect and that these mutations contribute together with defects in other pathways of B cell activation to the development of CVID. To test this hypothesis we propose to: 1. Examine whether ligand-independent ligand TACI oligomerization is required for subsequent ligand induced signaling, map the domain(s) that mediates the assembly of hTACI and probe the function of the short and long isoforms of hTACI. 2. Analyze whether the A181E TACI mutant exerts a DN effect in vitro in transfectants and patient B cells, and in vivo in knock-in mice. 3. Determine the effect of TACI mutations on its synergy with CD40 and TLRs in vitro and in vivo in TACI mutant mice, and investigate whether TACI mutations cooperate with mutations in the CD40 and TLR4 pathways to severely impair B cell function as observed in CVID. The studies proposed will help us understand the molecular mechanisms by which TACI mutations may contribute to B cell dysfunction in CVID. They are also critical for understanding the etiology of CVID and its complications (autoimmunity and lymphoma) and for devising novel therapies for affected patients. RELEVANCE (Seeinstructions): Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in humans. Patients with CVID suffer from recurrent infections and have an increased incidence of autoimmune disorders and lymphoid malignancies. The studies proposed are critical for understanding the etiology of CVID and of its complications (autoimmunity and lymphoma) and for devising novel therapies for affected patients.